Recent progress in the understanding of the regulatory and effector mechanisms of T and B lymphocytes suggests that specific tolerance to an allograft in man might be possible. There is evidence that the receptors for antigen on both T an B lymphocytes are themselves unique antigenic determinants, or "idiotypes," and that an animal is capable of making an immunological response to its own idiotypes. Cells mediating anti-idiotypic responses may suppress specifically immune responses by the clone of T-cells bearing the idiotypic receptor for a transplantation antigen. This suggests that by generation of appropriate anti-idiotypic suppressor cells in an allograft recipient it may be possible to suppress, deliverately and selectively, those T-cell clones reactive to donor major and minor histocompatibility antigens. This project is designed to explore anti-idiotypic responses and assess the clinical potential of this approach to immunological tolerance. Ten experimental protocols are described to explore active and passive induction of anti-idiotypic suppression in the mouse, in a canine model, and in vitro with human cells. The study will examine suppression of both primary and secondary immune responses, the effects on responses to both major and minor histocompatibility antigens, and the correlation between in vivo responses (murine skin allografts and canine renal allografts) and in vitro responses (mixed lymphocyte reactivity and cell-mediated lympholysis). Additional experiments will examine the relationship of cytotoxic effector T-cells and allograft rejection. The ultimate objective of the project is to develop appropriate protocols for induction of anti-idiotypic suppressor cell-mediated tolerance in clinical transplantation.